Apparatus and Method for Generating Nitric Oxide in Controlled and Accurate Amounts

ABSTRACT

A nitric oxide generator generates nitric oxide from a mixture of nitrogen and oxygen such as air treated by a pulsating electrical discharge. The desired concentration of nitric oxide is obtained by controlling at least one of a frequency of the pulsating electrical discharge and duration of each electrical discharge pulse.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/887,246, filed Feb. 2, 2018, which is a divisional of U.S.application Ser. No. 15/372,552, filed Dec. 8, 2016 (now U.S. Pat. No.9,896,337, issued Feb. 20, 2018), which is a divisional of U.S.application Ser. No. 14/347,479, filed Mar. 26, 2014 (now U.S. Pat. No.9,573,110, issued Feb. 21, 2017), which is a US National stage entry ofInternational Application No. PCT/US2012/058564, which designated theUnited States and was filed on Oct. 3, 2012, published in English, whichclaims the benefit of U.S. Provisional Application No. 61/542,400, filedon Oct. 3, 2011. The entire teachings of the above applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention discloses a method and apparatus for the production ofnitric oxide (NO) in controlled and accurate amounts, with low levels ofimpurities by controlling electric discharges between two electrodes inan oxygen nitrogen gas mixture.

Nitric oxide is known to have many applications in biological systems ofboth plants and animals.

In plants it is known that modifying the local atmospheric concentrationof nitric oxide can stimulate a number of beneficial effects including,improved growth (U.S. Pat. No. 6,242,384), reduction in seed dormancy(Bethke, 2006 and Sarath, 2006), protection from fungal infections anddisease (Lazar, 2008 and Hong, 2007) and preservation of cut flowers andfruit (U.S. Pat. Nos. 6,451,363 and 6,720,017).

In medical applications, gaseous nitric oxide administered to thepatient is known to have multiple applications as disclosed in thefollowing examples.

Anti-microbial: Nitric oxide has been demonstrated to reduce bacterialinfections as shown during in-vitro testing (Ghaffari, 2006) and inclinical applications such as skin tissue infections (Ghaffari, 2007)and cystic fibrosis lung infections (Sagel, 2009).

Wound Healing: Nitric oxide has been demonstrated to improve healingtimes in both sterile and infected wounds (Shekhter, 2005).

Hemoglobinopathy: (U.S. Pat. No. 5,885,621) with application in sicklecell disease, where nitric oxide significantly reduced pain associatedwith vaso-occlusive crisis in sickle cell patients as compared toplacebo (Head, 2010).

Selective pulmonary vasodilatation: (U.S. Pat. No. 5,485,827) withapplication in hypoxic respiratory failure of the newborn, where nitricoxide therapy selectively dilates the pulmonary vasculature and improvesoxygenation, with no negative impact on systemic blood pressure (Clark,2000).

Anti-inflammatory: (U.S. Pat. No. 6,656,452) with application inreducing ischemia reperfusion injury and the infarct size aftermyocardial infarction (Liu, 2007).

It is clear that with all these potential commercial applications thatmake use of the biological effects of nitric oxide, there needs to be anapparatus to deliver nitric oxide in an accurate and controlled amountthat is reliable and efficient. One issue that has to be taken intoaccount when considering a method of nitric oxide delivery is that ofnitrogen dioxide (NO₂) generation. Nitric oxide, when in the presence ofoxygen, reacts to form nitrogen dioxide, which is am irritant tobiological systems. To resolve this issue, there are two main approachesfor generating and then controlling the delivery of nitric oxide tobiological systems. A first approach is to produce nitric oxide fromchemical precursors, for example, through the oxidation of ammonia andto store the nitric oxide with a diluent gas that does not containoxygen (the gas used is normally nitrogen) in a high pressure cylinder.As the nitric oxide is needed, a delivery system (for example, ametering valve) controls the flow of nitric oxide gas from the cylinderto provide the amount of nitric oxide needed for any given application.The benefit of this approach is that it is relatively easy to controlthe amount of nitric oxide gas needed for a specific application and thepurity of the nitric oxide can be ensured by a well controlledproduction process in a centralized production manufacturing location.The main problem with this approach is that the cylinders of compressednitric oxide gas are large and heavy and are logistically difficult andexpensive to ship from the centralized location to the site ofapplication.

A second approach is to generate the nitric oxide gas in-situ from roomair, using a controlled electric discharge to ionize the gas at alocally higher temperature to form a plasma, where oxygen and nitrogenin the air break down and reform to produce nitric oxide. This nitricoxide generating approach has the advantage that it does not have thelogistical problems of the gas cylinder storage method. It is however,more difficult to accurately and controllably produce the requiredamounts of nitric oxide with the required purity.

Before providing a description of the invention an overview ofbackground art will be described.

The use of electric discharges to produce nitric oxide in a plasmareaction has a long history, a good summary of which is included in U.S.Pat. No. 4,287,040 by Alamaro. This early prior art was focused on thebulk production of nitric oxide as an intermediary to the production ofnitrogen based fertilizers and describes a process that is not concernedwith the accuracy, purity and safety of the nitric oxide generated.

U.S. Pat. No. 5,396,882 (Zapol) was the first to disclose a system forproducing nitric oxide by electric discharge for use in medicine. Inthis method, there is an electrically insulated reaction chamber where ahigh voltage circuit is used to induce an electric arc discharge betweentwo electrodes that are separated by an air gap to produce nitric oxide.The patent discloses gas filters in the inlet conduit to the reactionchamber to remove liquid droplets or solid particles from entering thereaction chamber, and a soda lime filter in the outlet conduit of thereactor chamber for removing impurities such as nitrogen dioxide thatmay be formed in the plasma along with the nitric oxide. Also describedis a gas analyzer such as a chemiluminescence analyzer for measuring theamount of nitric oxide produced. The high voltage circuit includes astep up transformer, which takes standard AC power of 110V and 60 Hz(230V and 50 Hz in Europe) in the primary coil, and steps up the voltageso that the peak voltage is sufficient to induce an electric arc acrossthe electrode air gap. There is a capacitor on the secondary side of thetransformer, which is charged up to the breakdown voltage, andsubsequently discharged across the gap when the breakdown voltage isreached. The current to the primary side of the transformer is regulatedby an autotransformer (Variac), which controls the power to thecapacitor and hence on to the electric arc discharge. The current fromthe capacitor is not controlled once break down voltage has occurred,and this results in an arc discharge which is quick and intense with ahigh current and high gas temperatures. The system describes producingnitric oxide continuously and controls the amount generated bycontrolling the current to the transformer, it also describescontrolling the amount of diluting gas flow to provide the desiredconcentration.

There are a number of problems with this type of system which include:electric arc discharges cause high current at high temperatures whichcause vaporization of the electrode material which leads to excessivewear of the electrodes. Electrode wear is a function of the intensity ofthe discharge across the electrodes, which translates into the higherthe current the higher the electrode wear. The high temperature can alsoresult in higher levels of nitrogen dioxide being formed, which is notdesired in a number of biological applications. In addition, due to theelectrode wear, the amount of nitric oxide generated in this system isnot accurately predictable over periods of time and it requires a nitricoxide gas analyzer to ensure the expected amount of nitric oxide isbeing generated accurately. A gas analyzer adds expense, bulk andrequires the user to calibrate it prior to use, which makes itundesirable for an optimum nitric oxide generation system. The patentdiscloses a filter for removing nitrogen dioxide from the nitric oxidegas mixture. However the soda lime filter material disclosed has afinite life, and if it is not changed when the life of the filtermaterial is exhausted, the system would allow the nitrogen dioxide to bedelivered to the biological system, and this could result in harm to thebiological system.

In EP 0719159 (Jacobson), the problem of high energy arc dischargeseroding the electrodes was addressed by disclosing a method ofcontrolling the current across the air gap to a low level to produce a“glow discharge” to produce nitric oxide. The invention describedmultiple ways of initiating the glow discharge such as; using a separatehigh voltage spark circuit, reducing the pressure in the chamber orinitially bringing the two electrodes closer together to initiate thespark. Once the glow discharge was established it was continuouslymaintained. To control the nitric oxide concentration to be delivered tothe biological system the nitric oxide output was diluted withadditional gas flow. The disadvantages of this approach are that thereis a limited range of current that allows a glow discharge to be formed,and once formed the glow discharge needs to be continuously maintained.This limits the controllable range of the nitric oxide that can beproduced. The required nitric oxide concentration to the biologicalsystem is achieved through diluting the nitric oxide flow from thereactor chamber with an additional diluting gas flow. However, thismeans both the gas flow rate and nitric oxide concentration cannot becontrolled independently. If lower concentrations of nitric oxide at lowgas flow rates are required, then a large portion of the nitric oxidegenerated is discarded resulting in low efficiency of operation and anadditional apparatus associated with safely disposing of the unusednitric oxide gas flow.

U.S. Pat. Nos. 6,296,827 & 6,955,790 (Castor, et al.) disclose analternative approach to avoiding electrode wear due to high energy arcdischarges. These patents disclose an apparatus where a dielectricbarrier material covers one of the electrodes and a corona discharge isproduced in high frequency discharge pulses to avoid electrode wear. Thereactor chamber has to be operated between 400° C. and 800° C. so thenon-thermal plasma generates nitric oxide instead of nitrogen dioxide(NO₂). The device also discloses the use of a catalyst operated at anelevated temperature to convert any NO₂ formed to nitric oxide. Thetemperature in the reactor is kept below 800° C. to avoid electrodeerosion caused by oxygen radicals and above 400° C. to avoid NO₂ beingformed instead of nitric oxide. The apparatus disclosed that the nitricoxide gas flow is diluted by additional gas to produce the desiredconcentration of nitric oxide that is needed clinically. Thedisadvantage of this apparatus is that it requires extra electricalpower to heat the gas to 400° C. to 800° C. and then requires the gas tobe actively cooled after the reactor chamber before it can be usedclinically. This significantly increases the power and complexity of theapparatus. It also has the same problem as EP 0719159, in that itprovides a limited controllable range of nitric oxide being produced,and also relies on gas dilution to produce the desired nitric oxideconcentration. Therefore it has the same limitation as described in EP0719159 in that in some applications, it will result in unwanted nitricoxide gas flow that will need to be discarded resulting in inefficientoperation and the need for additional apparatus for the safe disposal ofthe unused nitric oxide.

U.S. Pat. No. 7,498,000 (Pekshev, et al.) discloses a device for forminga nitric oxide containing gas flow using a continuous stationary DC arcdischarge. The arc discharge is maintained at a constant voltage levelof approximately 120V at 2.3 A, which maintains an arc temperature of3500° K. to 4000° K. The gas flow is then quenched in a water ethanolcooled chamber where it is rapidly cooled to approximately 1000° K. tofix the nitric oxide that was generated in the arc discharge, it thengoes on to a further cooling area where it is cooled to a temperature of150° C. before it exits the outlet. The arc discharge is initiated witha high voltage spark discharge from a 5 kV circuit, and uses astabilization electrode to maintain the arc discharge. The nitric oxidegas concentration at the apparatus outlet is shown in FIG. 14 as 4,000ppm nitric oxide, and the concentration is shown to decrease as afunction of the distance from the outlet, dropping to about 500 ppmnitric oxide at a distance of 200 mm. This drop in nitric oxideconcentration is due to the gas mixing with ambient air, and means alarge part of the nitric oxide generated never gets to the intendedbiological target. It also means the user has to be very careful aboutthe distance of the apparatus outlet to the biological target so theintended nitric oxide concentration is delivered correctly. Theapparatus disclosed has the same problems as previous art in that theamount of nitric oxide generated is not well controlled and relies onwasteful dilution of the nitric oxide prior to delivery to thebiological target. In addition there is no effort made to remove harmfulNO₂ that will also be formed in the arc discharge.

The prior art have the following disadvantages:

1) The prior art does not disclose apparatus that can control the amountof nitric oxide over a wide range of gas flows and nitric oxideconcentrations so that the device can be used for multiple distinctdosing regimens depending on the target application.

2) The prior art does not disclose apparatus that allows for a widerange of nitric oxide outputs without requiring additional gas flowdilution. This results in excess nitric oxide generation that has to besafely disposed of, causing extra cost and complexity.

3) The prior art that uses high voltage electric arc discharges togenerate nitric oxide has high electrode wear due to electrodevaporization caused by the intense electric arc discharges.

4) The prior art that uses corona discharges require high reactionchamber temperatures to be maintained that needs additional power, andthen require gas cooling systems to bring the gas flow back down toacceptable temperature levels prior to administration, thus adding tothe cost, complexity and poor efficiency of the system.

5) None of the prior art provides a simple way of monitoring the correctfunctioning of the arc discharge so the amount of nitric oxide generatedcan be accurately predicted.

6) None of the prior art discloses a consumable filter for removing NO₂and other adulterants from the nitric oxide gas flow that when consumed,can provide the nitric oxide apparatus with a means of alerting the userthat it needs to be replaced.

SUMMARY OF THE INVENTION

The present inventors have identified the above disadvantages and theinvention described in this specification provides solutions to theabove disadvantages and discloses methods and apparatus for the accurateproduction of nitric oxide over a wide range of output in a reliable andefficient way.

A feature of at least one embodiment of the invention is to provide animproved apparatus and method for the generation of nitric oxide using agas plasma produced by electric discharges across two electrodes, whichovercome the disadvantages previously described in the prior art. Insolving the disadvantages of the previously described prior art, theinvention makes it particularly appropriate for treating biologicalsystems with nitric oxide that is both accurately controlled and thatensures low levels of impurities.

At least one embodiment of the invention includes a reactor chamber witha gas inlet for a gas flow of air, or other oxygen and nitrogencontaining gases, to enter the reactor chamber, two electrodes separatedby a gap, an electronic control circuit connected to the electrodes togenerate an electric discharge across the gap to produce nitric oxide,and an outlet for the nitric oxide containing gas mixture to exit thechamber.

One embodiment of the invention produces nitric oxide in accuratelycontrolled amounts over a wide range of gas flow rates and nitric oxideconcentrations by controlling one or both of the pulse frequency (numberof complete electric discharges per second) and/or the pulse duration(length of each complete electric discharge) of electric pulsedischarges across the electrode gap. The amount of nitric oxidegenerated is proportional to both the frequency and the duration of theelectric pulse discharges and so either one by itself of in combinationwith the two can provide a wide control range of nitric oxidegeneration.

In one embodiment of the invention, the electronic control circuitstarts each electric discharge pulse with a short phase of high voltageto initially ionize the gases and to allow electric current to startflowing across the electrode gap, this is then followed by a secondphase of the pulse, which is of a lower voltage and current. In oneembodiment of the invention, the first high voltage phase of the pulseis kept to a small period of time that is just long enough to initiallyionize the gases between the electrodes and to allow electric current toflow in the electrode gap. In the second phase of the pulse the voltageand the current is reduced to lower values and this phase corresponds tothe adjustable duration phase of the electric pulse discharge. In oneembodiment of the invention the apparatus is designed so that themajority of the nitric oxide is generated during the more efficientsecond phase. There are a number of stable voltage and currentcombinations that can be used in this second phase of discharge and theyhave different advantages and disadvantages. This type of electricdischarge with intermittent pulse operation with controlled frequencyand/or duration at a controlled, predominantly low current providesbenefits including:

It produces nitric oxide efficiently by only producing the amount ofnitric oxide needed for the application without the need for additionaldiluent gases.

It produces nitric oxide without significant increase in the temperatureof the gases going to the biological system and therefore does not needcooling apparatus.

It significantly reduces electrode wear due to vaporization of theelectrode because the average electric current is low.

The low current and intermittent pulse electric discharge generatesnitric oxide efficiently without generating high levels of NO₂.

Another desired feature of at least one embodiment of the invention isto generate nitric oxide more efficiently with lower power consumption.One novel approach used in one embodiment of the invention to improvethe nitric oxide generating efficiency is to provide a magnetic fieldacross the electrode gap. This can be achieved by using either electriccoils or permanent magnets to provide the magnetic field across theelectrode gap. With a magnetic field crossing perpendicular to the gap,an increase in the quantity of nitric oxide generated of up to 45% forthe same electric discharge pulse settings was shown. Specific examplesof improved efficiency will be given in the detailed description sectionof the invention.

Another feature of a nitric oxide generation apparatus useful withbiological systems is that undesirable changes in the amount of nitricoxide generated may be anticipated to alert the user to the alarmcondition. The alarm can be an audio or visual indicator or an externalsignal so that corrective action can be taken such as getting areplacement nitric oxide generation system. Examples of the typical kindof failures that can cause the nitric oxide generation apparatus to stopfunctioning or to only produce partial nitric oxide output are asfollows:

The electrode gap becomes larger due to wear over time.

The electrical insulation in the high voltage circuit breaks down andcauses the electric charge to leak to ground without passing through theelectrodes.

A component failure in electronic control circuit due to electromagneticpulses from the electric discharges.

A power supply failure to the electronic control circuit.

The gas flow through the reaction chamber is higher or lower thandesired.

In the prior art this was achieved with a nitric oxide gas monitor,however the problem with this approach is that gas monitors are complex,bulky and require periodic calibration by the user adding to the overallcomplexity of use. In one embodiment of the invention the need for gasmonitoring is alleviated by independently monitoring the pulse frequencyand pulse duration of the electric discharge in the reaction chamber andhaving a flow sensor to redundantly monitor the gas flow through thereaction chamber. The basic physics of gas plasma reactions is wellunderstood and if there is an independent sensor that monitors thefrequency and the duration of the electric discharge pulse then thecorrect amount of nitric oxide being generated can be accuratelypredicted. A number of different sensing technologies can be used toindependently monitor the electric discharge.

The discharge monitor sensor can be a photodiode in optical connectionto the reaction chamber, which monitors the light generated by theelectric discharge. The frequency and duration of the light emitted bythe electric discharge pulse and detected by the photodiode will be inproportion to the electric discharge pulse. If there is not a dischargepulse, or if it is intermittent, or a different duration, then thephotodiode will detect the malfunction and cause an alarm. In oneembodiment, the photodiode may be used to provide feedback correction ofthe electric discharge pulse to ensure consistent arc length andduration.

The discharge monitor sensor can also be an electric current or voltagesensor that monitors the electric current or voltage across theelectrode gap when the pulse occurs to determine the frequency andduration.

The discharge monitor sensor could also be a field effect (Hall Effect)transducer that monitors the magnetic field or flux across the electrodegap when the discharge pulse occurs. The transducer can monitor magneticfield/flux that occurs when an electrical discharge pulse is takingplace, and its frequency and duration can be monitored and an alarmgenerated if a malfunction has occurred.

As well as monitoring the electric discharge is producing the correctamount of nitric oxide, the apparatus may also monitors the air flowrate through the reaction chamber with a gas flow sensor. This ensuresthat the nitric oxide generated by the apparatus is being delivered fromthe reaction chamber to the biological system at the require flow rate.If the apparatus is set to deliver a specific gas flow rate at aspecific nitric oxide concentration, then the combination of thedischarge monitor sensor (to determine the amount of nitric oxide beingproduced) and the gas flow sensor can be used to ensure the nitric oxideconcentration is correct to the set level and provide an alarm ifincorrect.

Another requirement is that adulterants such as NO₂ are kept atacceptable level s when nitric oxide is being delivered to a biologicalsystem. Previous prior art have described filters that can be attachedto the outlet of the device that can either convert NO₂ to nitric oxideor to remove NO₂ from the gas stream. The problem with these filters isthey have a finite life that is dependent on how much NO₂ they areexposed to. If the user does not replace them when they are consumed,then the biological system may be unintentionally exposed to levels ofadulterants that can cause harm to the biological system. One embodimentof the invention provides a novel way to ensure that the user isinformed when the filter is approaching its expiry limit and when it isfully expired. It may also stop delivering nitric oxide when the filteris expired if the biological system is especially sensitive to thelevels of NO₂ that may be present without the filter.

One embodiment of the nitric oxide generation apparatus has a machinereadable and programmable interface between the apparatus and the filterand this interface communicates with a non-volatile programmable andreadable memory device located in the filter assembly. The filter memorydevice can be programmed during manufacturing with a number ofparameters that can be read by the nitric oxide generation apparatuswhen it is attached to the device. These parameters can include thecapacity of the filter in hours, or in hours per quantity of nitricoxide (NO₂ is produced in amounts proportional to the amount of nitricoxide generated) that is being delivered, and that the filter has beenshown to remove adulterants effectively. As the filter is consumed, thefilter programmable memory is updated with data that allows theremaining capacity of the filter to be determined by the nitric oxidegeneration apparatus. For instance, the filter memory can be updatedperiodically with the new current filter capacity based on the originalfilter capacity and the amount of time the nitric oxide generationapparatus has been in use at a particular nitric oxide setting. Thismeans the filter always has an accurate representation of the remainingcapacity programmed into the filter memory. This has the advantage thata completely used up filter can not be accidentally put on the same oreven a different device at some point in the future resulting in thebiological system getting exposed to high levels of adulterants. Thereare a number of programmable memory technologies that could be used forthis function. Two examples include EEPROM (electrically erasableprogrammable read only memory) and FLASH, which was developed fromEEPROM and must be erased in fairly large blocks before these can berewritten with new data. One embodiment of this invention uses an EEPROMwith a serial interface for reading and reprogramming the memory.Another embodiment uses a micro-controller which includes EEPROM andFLASH memory and communicates to the nitric oxide generator device by aserial interface. However, the invention is not meant to be limited tothese specific types of memory technology and could equally apply toother types of programmable memory.

As well as the filter life/capacity parameter there can also be otheruseful parameters programmed into the filter that can greatly simplifythe setup and use of the apparatus. One set of parameters that couldalso be programmed into the filter memory can be related to the dosinginformation for the particular biological system treatment regime. Thiscould include the dose setting in nmoles/sec, ppm at the desired flowrate through the reaction chamber to the nitric oxide applicator, andthe treatment time for which the dose should be applied. The filter(with memory) can be packaged and attached to the nitric oxideapplicator for a particular application so a user can simply open theapplicator package and connect it to the nitric oxide generationapparatus. All the dose settings would be read automatically from thefilter memory when it is attached to update the apparatus settings priorto use. Each application could have a custom applicator that isoptimized for that biological system with the correct sized filter forthe required dose and duration. The dose parameters can in some cases beset to zero if the biological application is to be used in a blindedplacebo controlled study where some subjects would get nitric oxide andsome would only get a flow of gas. In these cases the apparatus displaywould not display the actual dose setting but would be blank or loadedwith a dummy setting so the user would not know which dosing regimenthey were on. For added protection against un-blinding a study, thesedose parameters could be encrypted at the factory and then de-encryptedby the device when the filter was connected. The encryption wouldprevent users from effectively reading the filter dose parameters with amemory programming tool prior to use. This means a single nitric oxidegenerating apparatus can have wide spread application with no changes tothe device itself, with only the nitric oxide applicators beingcustomized for the specific biological system.

Another set of parameters that can be programmed into the filter memorythat are specific to individual biological systems can revolve aroundthe proper functions of the apparatus. These parameters can set whatalarms will be present for different detected conditions, and whetherthey will involve audible and/or visual alarms and/or if the deviceshould stop generating nitric oxide and stop gas flow through thereaction chamber when these conditions occur. The conditions that can bedetected by the apparatus can include the following possible faultconditions:

1) The flow through the reaction chamber is lower or higher than the setvalue.

2) The NO₂ filter has no hours/capacity left or is approaching thatcondition.

3) The electric discharge pulses are not at the desired frequency orduration for the dose setting resulting in either too high or too lowdoses to the biological system.

The filter memory can be programmed with not only what type of alarmshould be activated when these conditions occur but also the alarmlimits that will cause the alarms to be initiated. This can allow verysensitive biological systems that need very tight dosing specificationsto have tight alarm initiating limits and those that only require looselimits can have them set accordingly.

Yet another set of parameters that can be programmed into the filtermemory are what user adjustable settings may be active on the nitricoxide generating apparatus user interface. For instance some biologicalsystems may require the dose to be slowly reduced over time as thebiological system responds to treatment, or depending on the size of thebiological system, the gas flow rate through the chamber may need to beadjusted for the different system size. In another option, it may beadvantageous to allow the user to set the alarm limits for the gas flowor the nitric oxide concentration. The description in this specificationof the possible parameters that can be stored in the filter memory for agiven custom biological system application is not meant to be exhaustivebut allows the concept of custom parameters to be described.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a cross-sectional view of the reactor chamber showing the maincomponents of the reactor chamber design.

FIG. 2 is a schematic diagram of the nitric oxide generator showing thecomponents of the system and their electrical and pneumatic connections.

FIG. 3 is an electronic schematic of the pulsed electric discharge drivecircuit.

FIG. 4 is a graph that illustrates the wide performance range of thesystem with the amount of nitric oxide being generated varying from 0.27to 711 nanamoles/second nM/s.

FIG. 5 is a graph that illustrates the improved generation of nitricoxide when a magnetic field is used in the design.

FIG. 6 is a graph that illustrates the removal of NO₂ by a filter.

These figures will now be described in more detail.

DETAILED DESCRIPTION OF THE INVENTION

In the following detailed description the term “air” will be used togenerally describe the oxygen and nitrogen gas mixture used in reactorchamber to generate nitric oxide, but also other gas mixtures containingoxygen and nitrogen that may have been produced from alternative gassources such gas cylinders that are commonly used in anesthesia machinesand may include alternate concentrations.

FIG. 1 shows the nitric oxide reactor chamber 1 with a reactor housing 2which has a reactor gas inlet port 8 and a first electrode 12 on oneside and a reactor gas outlet port 10 and a second electrode 20 on theother side. The electrodes can be insulated with non-electricallyconducting material 14 and 22 if the chamber housing is made of amaterial that is electrically conducting. The electrodes can have anelectrode tip 16 and 24 made of a material that is resistant to hightemperatures and is less susceptible to vaporization, oxidization andwear. Materials for the electrode tips can be selected from the Nobelmetal group of the periodic table that includes tungsten and platinum.The electrodes are connected to the electronic control circuit with theinsulated electrical cables 18 and 26.

In one embodiment of the invention the reactor chamber can have magnets30 and 32 located on the reactor housing 2 so they are adjacent to theair gap between the electrodes 12 and 20, each magnet with the oppositepole facing the chamber so they reinforce the magnetic field across theair gap. One embodiment of the invention has a magnet on each side ofthe air gap although a single stronger magnet that exerts the samemagnetic field strength across the air gap is equally applicable. Themagnetic field across the air gap is believed to cause dispersal of theelectrical discharges across the air gap, which results in a largerplasma cross-sectional area and more efficient generation of nitricoxide. In one embodiment the magnets are rare earth magnets made fromneodymium iron and boron. In testing, the addition of magnets resultedin approximately 45% more nitric oxide being generated for exactly thesame pulse discharge settings as without magnets (FIG. 5).

The reactor housing 2 can have a port 34 that allows a photodiode 38 tobe in optical communication with the inside of the reactor chamber 1.The optical communication can be provided so the photodiode is mounteddirectly to the port 34 in the reactor housing or more preferably afiber optic cable 36 is mounted to the reactor chamber port and then tothe photodiode so said photodiode can be located away from the reactorchamber and the electrical disturbances cause by the pulse electricdischarges. The photodiode 38 provides a signal that is proportional tothe light energy falling on its active surface. When the pulsed electricdischarges occur, light is generated in the ionized plasma and thephotodiode detects this light. The light signal from the photodiodeoccurs at the same frequency and pulse duration as the electricdischarge as long as the discharge takes place.

FIG. 2 is a schematic diagram of the nitric oxide generator. There arethree main subsystems that make up the nitric oxide generator, thenitric oxide generator unit 50, the outlet filter assembly 78 and thenitric oxide applicator 84. The nitric oxide generator unit is where thenitric oxide is generated in controlled amounts and where it isdelivered to the generator gas outlet port 76. The generator unit 50 hasa main electronic control circuit 60 that interfaces to the mainelectrical components of the system and provides the main system controlfeatures. In one embodiment of the invention this is a microprocessorbased control circuit executing a stored program held in a nontransitory medium, but it is not intended to limit the invention only tomicroprocessor based control circuits, analog circuits could also beused. Attached to the electronic control circuit are the main usercontrols comprising of an input setting unit 52 a visual display unit54, a visual alarm indicator 56 and an audible alarm sounder 58, thesecomponents are used to provide the desired settings to the main control,display any preprogrammed settings that may have been automatically setfrom the preprogrammed filter memory and provide audible and visualalarms when there are fault conditions. The main components in contactwith the air flow though the device are, the generator gas inlet 62where the air is drawn into the unit, the inlet filter 64 which is usedto filter the air and remove any unwanted contaminants, the air pump 66is used to draw the air in from the gas inlet port 62 and to adjust theamount of air flow that is passed through the reactor chamber 1 underthe control of the electronic control circuit 60. If the air pump 66provides un-calibrated control of the gas flow, a gas flow meter 70 canbe used to provide the electronic control circuit an accurate indicationof the gas flow so the pump can be finely adjusted by the electroniccontrol circuit 60 until the gas flow is at the desired set value. Ifthe gas pump 66 provides oscillatory gas flow output as in the case of apiston pump then a damping chamber 68 can be provided to smooth out theoscillations. The gas flow then passes through the reaction chamber 1where the electric control circuit 60 controls the frequency andduration of the electric discharges across the electrodes 12 and 20 suchthat nitric oxide is generated in the air passing through the chamber.The gas leaving the reaction chamber 1 passes through a second flowmeter 72, which is used by the electronic control circuit to provide anindependent check that the flow through the reaction chamber is correct.If there has been a failure in the gas pump 66 (indicated by a zero flowrate) or the first flow meter 70 or 72 (indicated by different readingsbetween flow meter 70 and flow meter 72) such that the gas flow throughthe reaction chamber is not correct, then the electronic control circuitcan initiate a visual and/or audible alarm to alert the user to thefailure. To detect if there has been a failure in the electric dischargecircuits there is the photodiode 38 and/or the electrode current and/orvoltage sensing circuit 61 that are connected to the electronic controlcircuit 60, which can determine if the right frequency and pulseduration has been achieved. After the outlet gas flow meter 72 there isan optional pressure trigger sensor 74 connected to the gas flow conduit73. This pressure trigger sensor 74 can be used by the electroniccontrol circuit 60 to control the nitric oxide delivery as a bolus (whenthe pressure trigger sensor is activated) rather than as a knownconcentration in a continuous gas flow rate of air. The different modesof delivery will be described in more detail later in the specification.The gas flow continues past the pressure trigger sensor 74 to the gasoutlet port 76, where it connects to the outlet filter assembly 78 andout through the nitric oxide applicator 84, where it is applied to thebiological system 92.

The outlet filter assembly 78 has an inlet filter port 80, whichconnects to the gas outlet port of the nitric oxide generator unit 50, achamber containing adulterant filter material 82, and an outlet port 86,which connects to the nitric oxide applicator 84. Adulterant filtermaterials include materials such as soda lime, activated charcoal,activated alumina and silica gel soaked in ascorbic acid. Thesematerials and others known in the art to remove NO₂ from gasescontaining nitric oxide while leaving the nitric oxide levelssubstantially unchanged may be used.

Such materials may have a fixed capacity for removing or converting NO₂before there effectiveness is consumed and they therefore requirereplacing after a period of use. The size of the filter and the amountof NO₂ they are exposed to will impact the usage time before they needreplacing. The filter assembly 78 in addition includes a readableprogrammable memory 90, which connects to the nitric oxide generatorunit through a filter electrical connection 88. The other side ofconnector 88 connects to the electrical control circuit 60 where thereadable programmable memory 90 can be read and reprogrammed by theelectrical control circuit 60 as the filter is consumed. One embodimentof the readable programmable memory is an EEPROM, which has a serialinterface for reading and programming the memory. An alternativeembodiment is where each individual EEPROM (and hence filter assembly)has its own unique identifier included in a small amount of read onlymemory (ROM). An example of this type of memory is part number24AA02E48T from Microchip Technology, this is a 2KBIT EEPROM with eachmemory chip having its own MAC address permanently programmed into asmall section of read only memory. This type of EEPROM with its uniqueidentifier programmed into ROM means that no two filter assemblies willhave the same identifier and the identifier will not be able to beupdated during use as can occur with the data in the EEPROM memory. Thiscan provide additional protection against reusing spent filters, asindividual filter identifiers can be stored in the nitric oxidegenerator when they are used and then the generator will prevent filterswith the same identifiers being used in the future for example, as mightoccur if the EEPROM usage data were improperly altered by a corruptedsystem. An alternative embodiment is where a micro-controller withembedded EEPROM and FLASH memory is used instead of just a serial memorydevice. This embodiment has the advantage that the reprogramming of thememory can be performed locally by the micro-controller and reduce theprocessing overhead of the electronic control circuit 60. An example ofthis type of micro-controller is the ATtiny25/45/85 from Atmel.

Generally the EEPROM, may store usage information obtained from theelectronic control circuit 60 that reveals the historical concentrationsof NO being produced and thus the likely exhaustion rate of the filter82. Thus, when the filter 82 is used for high NO concentrations and/orhigh flow rates this will be recorded and the user instructed to replacethe filter more frequently than if the filter 82 is used for low NOconcentration and/or low flow rate applications. This exhaustioninformation may be derived both from the concentration value determinedby the electronic control 60 and the flow rates determined from flowsensors 72 and 70. The EEPROM may also include a proprietary codeindicating that it is authorized equipment preventing spoofing of theapparatus with devices that may not provide the desired filtering. Theproprietary code may, for example, use any number of techniquesincluding public-key encryption techniques that prevent easy duplicationof spurious codes.

FIG. 3 shows a schematic of the electric discharge drive circuit that ispart of the electronic control circuit 60. This represents oneembodiment of the drive circuit and people of ordinary skill in the artwill appreciate there are other circuit possibilities that can achievethe same function. To establish the high voltage required to initiallyionize the air between the electrodes 12 and 20, a capacitor dischargecircuit 116 discharges current through a transformer 118 when triggeredby a pulse trigger controller 114. This results in a high voltage on theother side of the transformer 118 which is sufficient to causedielectric breakdown and ionize the gas and initiate current across theelectrodes 12 and 20. The discharge pulse duration is maintained by asecond circuit, which is powered by a high voltage DC power supply 100.In the case that the instantaneous current draw is high, the DC powersupply 100 is buffered by a capacitor 102 to smooth out any high currentfluctuations. The DC voltage and current is controlled on or off by atransistor 104 that is controlled by a pulse duration control circuit112 which controls the pulse duration by controlling the on time of thetransistor. The drive circuit functions as follows, the electroniccontrol circuit 60 calculates the desired electric discharge frequencyand pulse duration that will generate the desired quantity of nitricoxide, it then triggers each discharge with the pulse trigger controller114 which causes a quick high voltage pulse from the transformer 118, atthe same time the electronic control circuit turns on the transistor 104for the desired pulse duration with the pulse duration control circuit112. The resulting pulse discharge voltage across the electrodes is thedesired initial high voltage spike to ionize the gas between theelectrodes followed by the desired lower voltage and current formaintaining the desired pulse duration. The actual voltage and currentcan be controlled by the electronic control circuit 60 if the pulseduration control circuit 112 works in a pulse width modulation (PWM)mode during the on phase of the pulse discharge. If this PWM mode isused it is desirable to use an inductor 108 to smooth out the modulatedcurrent during the electric discharge pulse. The interface circuit 110joins the two control circuits prior to applying the discharge voltageto the electrode. It is desirable that this interface circuit 110 usehigh voltage diodes to prevent the high voltage spikes from the pulsetransformer damaging the transistor 104. The diode 106 provides anadditional mechanism that grounds any high voltage spike greater thanits breakdown voltage or negative transients from getting to the pulseduration control circuit 112. It can be appreciated that this circuitprovides a great deal of flexibility in controlling not only the pulsefrequency and the pulse duration but also the voltage and current levelsduring the pulse duration phase of the electric discharge. This allowsthe electronic control circuit to optimize the electric dischargefrequency and pulse duration settings to maximize the effectiveness atgenerating the desired quantity of nitric oxide while at the same timeminimizing the electric discharge current and so reducing the gastemperature and the electrode wear.

The pulses of electric discharge can be controlled over a wide rangedepending on the nitric oxide requirements; a frequency range of 0.1 to100 Hz with the pulse duration range between 0.1 to 10 milliseconds (ms)has been demonstrated. FIG. 4 shows a graph of nitric oxide output innM/s against the discharge frequency (Hz) for different pulse durationintervals from 0 up to 4 ms. It shows nitric oxide being generated from0.27 nM/s at 1 Hz and zero injection up to 711 MVPs at 22 Hz and 4 ms ofinjection. This example was where the high voltage DC power supply wasat 1,000 volts and the pulse duration control circuit operated in PWMmode so that the current across the electrodes was approximately 60 mA.These parameters can be programmed into the electronic control circuit,for example in a lookup table, so based on the required rate of nitricoxide generation, the correct frequency, duration and PWM control can beused. The values in the lookup table which map desired concentration tothe correct frequency and duration of the arc may be determinedempirically. In practice this means that nitric oxide concentrations canbe generated and controlled over the wide range of concentrations of 1to 1000 ppm in a flow rate in the range of 0.5 to 2 L/min depending onthe requirement of the biological system being treated.

A further improvement of at least one embodiment of the invention is theuse of a magnetic field to increase the amount of nitric oxide generatedby the apparatus. FIG. 5 shows a graph of the nitric oxide output fromthe apparatus in nM/s versus discharge frequency (Hz) for differentmagnetic fields. The parameters used for these tests were exactly thesame (PWM was set for electrode voltage 120V at a current 400 mA), withthe only difference being the number of magnets adjacent to theelectrode gap. As can be seen the nitric oxide output increases byapproximately 45% when four ½″ diameter rare earth magnets, two on eachside of the chamber housing, are used in the design compared to nomagnets. It is clear from FIG. 5 that as the number of magnets (andhence the magnetic field) increase, the amount of nitric oxide beinggenerated also increases.

The mode of operation will have some differences depending on the typeof biological system and what kind of dosing is required. There may besome modes where the gas flow through the system is at a constant flowrate and a constant concentration of nitric oxide for the application isrequired. In others a bolus mode of delivering the gas flow to thebiological system may be desired so an intermittent known quantity ofnitric oxide is required, for example nM/pulse. The intent is to beflexible so as to cover all the main permutations of these deliverymodes and how this is achieved is covered in the following.

In general the electronic control circuit 60 gets the desired settingfor the nitric oxide dose from the user setting unit 52, the readableprogrammable memory 90 on the filter assembly 78 or if it is a nitricoxide generator that is only configured for one specific applicationwith one dosing level then from the electronic control circuit's 60internal memory. The dose setting selected can be displayed on thedisplay unit 54 so the user knows the dose level that is to bedelivered.

The dose setting can be in different units depending on the mode ofdelivery, it can be set as a concentration such as parts per million(ppm) or micro liters per liter (uL/L), or it can be set as a quantityper unit of time such as nanomoles per second (nM/s) or nanomoles perminute (nM/min) or it can also be in terms of a quantity of nitric oxideto be delivered per event which will be described later in thespecification. The dose setting entered into the electronic controlcircuit 60 determines the required pulse frequency and pulse duration ofthe electric discharge to produce nitric oxide at the required rate.

If the dose setting was set as a concentration of nitric oxide at adesired airflow rate Q then the amount of nitric oxide in nM/s requiredto be generated in the gas flow can be calculated by equation 1.

rNO=(Q/60)·(C_(NO)*1000)Vm  Equation 1

Where rNO is the rate of nitric oxide production nM/s

Q is the gas flow rate (L/min)

C_(NO) is the concentration of nitric oxide (ppm)

Vm is the mole volume (approx 24.8 L/M at 25° C. 1 atm)

Once the rate of nitric oxide (rNO) has been calculated from the inputsettings, the required electric discharge frequency and pulse durationcan be determined by the electronic control circuit using the previouslydetermined relationship between the parameters (example FIG. 4) asenrolled in a lookup table in computer memory or implementedalgorithmically by an equation in computer memory. The required gas flowrate (Q) through the chamber is delivered from the gas pump 66 under thecontrol of the electronic control circuit 60. The flow meter 70 providesa signal proportional to the gas flow to the electronic control circuit60, which adjusts the gas pump control until the desired gas flow isachieved. The use of an air pump to provide the gas flow through thechamber is not the only means to provide the gas flow and it is beingused as an example. For instance if the air supply was from a pressurizepipeline or a gas cylinder then a control valve could be used to controlthe flow of gas instead of the air pump. Also, if it was required to addnitric oxide into an air flow stream that was being controlled byanother external device, then no control valve or air pump would berequired, in this case the gas flow meter 70 would be used to providethe electronic control circuit with the measurement of the air flow rateso the rate of nitric oxide generation can be determined. If theexternal flow control device has means to electronically communicate thegas flow measurement to the electronic control circuit then even the gasflow meter 70 is not needed for the correct functioning of theapparatus. With the desired gas flow rate established and the requiredelectric discharge frequency and pulse duration determined theelectronic control circuit 60 can initiate electric discharges acrossthe electrodes 12 and 20 and the nitric oxide containing gas will flowout through the gas outlet port 76.

When in the bolus mode of oxide delivery, the input setting unit 52 willbe used to enter the nitric oxide as a known quantity of nitric oxide inunits such as nano-moles (nM) or micrograms (μg) and also the volume ofthe gas to deliver the nitric oxide to the biological system. Theelectronic control circuit will determine the number and the duration ofelectric discharges required to produce that quantity of nitric oxide,and the bolus of nitric oxide will be generated and delivered when thepressure trigger sensor 74 is activated. One embodiment of the pressuretrigger sensor 74 is a pressure transducer with an adjustable limit toset the level that the trigger is activated. The pressure transducer canmeasure both positive and negative pressure relative to ambient and thetrigger to initiate the bolus delivery can also be a positive ornegative pressure.

For example, delivering nitric oxide to a cystic fibrosis patient wherethe application is to combat their lung infection. If the patient isbreathing spontaneously and the nitric oxide applicator is a nasalcannula connected to the patient's nose, then as the patient breathesin, the pressure in the nitric oxide applicator will go negativerelative to ambient and the pressure trigger sensor would need anegative pressure trigger setting to trigger the bolus so it goes to thepatients lung during inspiration. However, if the patient is on apositive pressure ventilator which has positive pressure in thebreathing circuit during inspiration, then the trigger setting limitwould require a positive pressure setting to trigger the bolus duringinspiration. When the pressure trigger sensor 74 is activated, theelectronic control circuit 60 initiates the electric discharge pulsesrequired to generate the nitric oxide set on the input setting unit 52and in addition the gas pump 66 is turned on to deliver the desiredvolume of gas set by the input setting unit 52 or programmable memory90, once the volume of gas has been delivered the gas pump is turned offagain. In this way a bolus of gas is delivered to the biological systemeach time the pressure trigger sensor 74 is activated and the bolus ofgas contains the desired set quantity of nitric oxide. In the case of apatient breathing normally in and out, the bolus of nitric oxide gascould be delivered to the patient at each breath. The nitric oxide gasleaves the nitric oxide generating unit at the gas outlet port 76 andgoes through the outlet filter assembly 78. The filter assembly 78 isattached to the outlet port 76 and the gas will flow through the filter82 where adulterants such as nitrogen dioxide (NO₂) are removed. As anexample of the effective performance of a filter in removingadulterant's an activated charcoal filter with 0.54 grams of materialwas assembled into a filter housing, the gas concentration of nitricoxide and nitrogen dioxide were analyzed over time before and after thefilter assembly. The conditions for the filter performance testing were225 ppm of nitric oxide at 2 L/min with 12 ppm of nitrogen dioxide inthe gas mixture. FIG. 6 shows a graph of the filter efficiency overtime, efficiency being defined as the percent of nitrogen dioxide in thegas being removed. The filter efficiency remained over 80% after 300minutes of continuous use under these test conditions.

After the filter, the nitric oxide gas flow passes into the nitric oxideapplicator 84, which conducts and applies the nitric oxide to thebiological system 92. There is a wide range of designs of nitric oxideapplicators that can be tailored for the wide range of potentialapplications in a wide range of biological systems. A few of thedifferent types of nitric oxide applicator will be described to provideexamples of the different types of applications that can be supported bythe nitric oxide generation device:

A piece of tubing, with a diffuser on the distal end that directs thenitric oxide gas flow directly to the surface of the biological system.An example is a tube with a diffuser to apply nitric oxide to anon-healing wound such as a diabetic ulcer.

A simple tube that connects to a chamber with the biological systempresent. Examples include a chamber that holds dormant wheat seeds thatcan be brought out of dormancy by exposure to nitric oxide or thechamber may be a sterilizing chamber where articles that arecontaminated with bacterial or fungus can be sterilized by exposure tonitric oxide.

A tube with a squeeze bulb in series that connects via a probe into achamber, which contains the biological system. The probe is connected tothe package and the bulb is squeezed which triggers the pressure triggersensor in the device to deliver a bolus of nitric oxide gas in to thepackage. Example, the chamber could be a gas tight plastic bag thatholds a modified atmosphere to ship cut flowers (e.g. tulips) and extendthe life of the product during shipping.

A tube connecting to a nasal cannula or a face mask that attaches to apatients nose/mouth to treat a patient with a lung infection such asoccurs in cystic fibrosis. The gas flows from the nitric oxideapplicator could be continuous flow at a set concentration or it couldbe pulsed as a bolus when the patient breathes in or out and triggersthe pressure trigger to deliver the bolus.

A tube that connects to a ventilator breathing system attached to apatient with a lung infection that triggers a bolus of nitric oxide whenthe pressure in the circuit increases during inspiration and triggers abolus delivery of nitric oxide.

These examples are not meant to include a comprehensive list of allpossible nitric oxide applicators but to give a general view of the widepotential of applications the nitric oxide generation apparatus can beused for.

1. (canceled)
 2. A nitric oxide generation system, comprising: a plasmachamber including two electrodes configured to generate a product gascontaining nitric oxide using a flow of a reactant gas through theplasma chamber; a controller configured to regulate the amount of nitricoxide generated in the product gas by the two electrodes in the plasmachamber using one or more parameters as input to a control algorithm, atleast one of the one or more parameters being related to the flow rateof the reactant gas into the plasma chamber; in input for connection toan external a pressurized reactant gas source to provide reactant gas tothe plasma chamber; a control valve positioned between the reactant gassource and the plasma chamber and configured to provide a flow of thereactant gas from the reactant gas source based on a measurementassociated with a medical gas into which the product gas flows; and afilter configured to remove NO₂ from the product gas generated by theplasma chamber, wherein the concentration of NO in the combined productgas and medical gas is a target value.
 3. The nitric oxide generationsystem of claim 2, wherein the measurement associated with the medicalgas is the flow rate of the medical gas such that the air flow of thereactant gas through the plasma chamber is proportional to the flow rateof the medical gas.
 4. A nitric oxide generation system, comprising: aplasma chamber including two electrodes configured to generate a productgas containing nitric oxide using a flow of a reactant gas through theplasma chamber; a controller configured to regulate the amount of nitricoxide generated in the product gas by the two electrodes in the plasmachamber using one or more parameters as input to a control algorithm, atleast one of the one or more parameters being related to the flow rateof the reactant gas into the plasma chamber; in input for connection toan external a pressurized reactant gas source to provide reactant gas tothe plasma chamber; and a control valve positioned between the reactantgas source and the plasma chamber and configured to provide a flow ofthe reactant gas from the reactant gas source based on a measurementassociated with a medical gas into which the product gas flows, whereinthe concentration of NO in the combined product gas and medical gas is atarget value.
 5. The nitric oxide generation system of claim 4, furthercomprising one or more filters configured to remove NO₂ from the productgas generated by the plasma chamber.